U.S. patent application number 10/427607 was filed with the patent office on 2004-02-05 for solvates and polymorphs of ritonavir and methods of making and using the same.
This patent application is currently assigned to Transform Pharmaceuticals, Inc.. Invention is credited to Almarsson, Orn, Morissette, Sherry L., Soukasene, Stephen.
Application Number | 20040024031 10/427607 |
Document ID | / |
Family ID | 31191043 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040024031 |
Kind Code |
A1 |
Morissette, Sherry L. ; et
al. |
February 5, 2004 |
Solvates and polymorphs of ritonavir and methods of making and
using the same
Abstract
Novel solvates and crystal polymorphs of Ritonavir are
disclosed, as well as methods of making them. Specific solvates of
the compound include a formamide solvate and a partially desolvated
solvate. Also disclosed are methods of making previously known
forms of Ritonavir. Methods of using the novel forms of Ritonavir
for the treatment of diseases, such as HIV-infection, are
disclosed, as are pharmaceutical compositions and unit dosage forms
comprising the novel forms of Ritonavir.
Inventors: |
Morissette, Sherry L.;
(Arlington, MA) ; Almarsson, Orn; (Shrewsbury,
MA) ; Soukasene, Stephen; (Boston, MA) |
Correspondence
Address: |
Transform Pharmaceuticals, Inc.
29 Hartwell Avenue
Lexington
MA
02421
US
|
Assignee: |
Transform Pharmaceuticals,
Inc.
Lexington
MA
|
Family ID: |
31191043 |
Appl. No.: |
10/427607 |
Filed: |
May 1, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60377211 |
May 3, 2002 |
|
|
|
Current U.S.
Class: |
514/365 ;
548/204 |
Current CPC
Class: |
A61K 45/06 20130101;
A61K 31/427 20130101; A61K 31/427 20130101; C07D 277/28 20130101;
A61K 2300/00 20130101 |
Class at
Publication: |
514/365 ;
548/204 |
International
Class: |
A61K 031/427; C07D
417/02 |
Claims
What is claimed is:
1. A composition comprising: a) ritonavir(III); b) a form of
Ritonavir which has a melting point of about 78.degree. C. to about
82.degree. C.; c) a form of Ritonavir which has a powder X-ray
diffraction pattem substantially the same as that shown in FIG. 8A;
d) a form of Ritonavir which has at least one unique powder X-ray
diffraction peaks selected from the group of: approximately 3.1,
6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees 2-Theta; e) a form
of Ritonavir which has at least two unique powder X-ray diffraction
peaks selected from the group of: approximately 3.1, 6.8, 7.7, 8.3,
9.2, 10.5, 12.1, and 13.1 degrees 2-Theta; f) a form of Ritonavir
which has at least three unique powder X-ray diffraction peaks
selected from the group of: approximately 3.1, 6.8, 7.7, 8.3, 9.2,
10.5, 12.1, and 13.1 degrees 2-Theta; g) a form of Ritonavir which
has at least four unique powder X-ray diffraction peaks selected
from the group of: approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5,
12.1, and 13.1 degrees 2-Theta; h) a form of Ritonavir which has at
least five unique powder X-ray diffraction peaks selected from the
group of: approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and
13.1 degrees 2-Theta; i) a form of Ritonavir which has at least six
unique powder X-ray diffraction peaks selected from the group of:
approximately 3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, and 13.1 degrees
2-Theta; j) ritonavir (IV); k) a form of Ritonavir which has a
melting point of about 97.degree. C. to about 101 .degree. C.; l) a
form of Ritonavir which has a powder X-ray diffraction pattern
substantially the same as that shown in FIG. 12A; m) a form of
Ritonavir which has at least one unique powder X-ray diffraction
peaks selected from the group consisting of: approximately 3.1,
6.1, 9.2, 12.1, and 13.8 degrees 2-Theta; n) a form of Ritonavir
which has at least two unique powder X-ray diffraction peaks
selected from the group consisting of: approximately 3.1, 6.1, 9.2,
12. 1, and 13.8 degrees 2-Theta; o) a form of Ritonavir which has
at least three unique powder X-ray diffraction peaks selected from
the group consisting of: approximately 3.1, 6.1, 9.2, 12.1, and
13.8 degrees 2-Theta; p) a form of Ritonavir which has at least
four unique powder X-ray diffraction peaks selected from the group
consisting of: approximately 3.1, 6.1, 9.2, 12. 1, and 13.8 degrees
2-Theta; q) a form of Ritonavir which has at least five unique
powder X-ray diffraction peaks selected from the group consisting
of: approximately 3.1, 6.1, 9.2, 12. 1, and 13.8 degrees 2-Theta;
r) a form of Ritonavir which has at least six unique powder X-ray
diffraction peaks selected from the group consisting of:
approximately 3.1, 6.1, 9.2, 12.1, and 13.8 degrees 2-Theta; s)
ritonavir(V); t) a form of Ritonavir which has a melting point of
from about 114.degree. C. to about 118.degree. C.; u) a form of
Ritonavir which has a powder X-ray diffraction pattern
substantially the same as that shown in FIG. 16A; v) a form of
Ritonavir which has unique powder X-ray diffraction peaks at
approximately 3.4, 6.4, 9.9, 12.7, 13.6, 15.3, 15.8, and 17.5
degrees 2-Theta; w) formamide, an immiscible or partially miscible
solvent, and Ritonavir; or x) acetate, acetonitrile, and
Ritonavir.
2. A method selected from: a) a method of preparing Ritonavir(III),
which comprises dissolving Ritonavir in a solvent system comprised
of formamide and an immiscible or partially miscible solvent to
provide a mixture, and.reducing the solubility of Ritonavir in the
mixture under conditions sufficient to provide Ritonavir(III); b) a
method of preparing Ritonavir(IV), which comprises partially
desolvating Ritonavir(III) to an extent sufficient to form
Ritonavir(IV); c) a method of preparing Ritonavir(V), which
comprises dissolving Ritonavir in a solvent system comprised of an
acetate and acetonitrile to provide a mixture, and reducing the
solubility of Ritonavir in the mixture under conditions sufficient
to provide Ritonavir(V); d) a method of preparing Ritonavir Form I,
which comprises desolvating Ritonavir(IV) for an amount of time
sufficient for the formation of Ritonavir Form I; e) the method of
claim (d), which comprises incubating Ritonavir(IV) in an aqueous
environment for an amount of time sufficient for the formation of
Ritonavir Form I; or f) a method of preparing Ritonavir Form II,
which comprises incubating Ritonavir(IV) in an aqueous environment
for an amount of time sufficient for the formation of Ritonavir
Form I and further incubating the Ritonavir Form I for an amount of
time sufficient for the formation of Ritonavir Form II.
3. A method selected from: a) a method of inhibiting HIV-1
protease, which comprises contacting HIV-1 protease with
Ritonavir(III), Ritonavir(IV), or Ritonavir(V); b) a method of
inhibiting HIV-2 protease, which comprises contacting HIV-2
protease with Ritonavir(III), Ritonavir(IV), or Ritonavir(V); c) a
method of treating, ameliorating, or managing HIV-infection, which
comprises administering to a patient in need of such treatment a
therapeutically effective amount of Ritonavir(III), Ritonavir(IV),
or Ritonavir(V); d) the method of claim (a), (b), or (c), wherein
the form of Ritonavir is Ritonavir(IV) or Ritonavir(V); e) the
method of claim (d) wherein the form of Ritonavir is Ritonavir(V);
f) the method of claim (a), (b), or (c), which further comprises
administering a therapeutically effective amount of a second
pharmacologically active compound to the patient; g) the method of
claim (f) wherein the second pharmacologically active compound is a
protease inhibitor, a nucleoside reverse transcriptase inhibitor,
or a non-nucleoside reverse transcriptase inhibitor, or a
pharmaceutically acceptable prodrug, salt, hydrate, solvate, or
polymorph thereof; h) the method of claim (g) wherein the protease
inhibitor is lopinavir, saquinavir, indinavir, nelfinavir,
amprenavir, palinavir, lasinavir, or tipranavir; i) the method of
claim (g) wherein the nucleoside reverse transcriptase inhibitor is
zidovudine, zalcitabine, lamivudine, didanosine, abacavir, tidoxil,
stavudine, adefovir, adefovir dipivoxil, or fozivudine; j) the
method of claim (g) wherein the non-nucleoside reverse
transcriptase inhibitor is delavirdine, efavirenz, immunocal,
loviride, nevirapine, or oltipraz; k) a method for improving the
pharmacokinetics of a pharmacologically active compound, which
comprises administering to a human in need of the pharmacologically
active compound a combination of a therapeutically effective amount
of Ritonavir(III), (IV), or (V), or a pharmaceutically acceptable
salt thereof, and a therapeutically effective amount of the
pharmacologically active compound, or a pharmaceutically acceptable
prodrug, salt, hydrate, solvate, or polymorph thereof, wherein the
pharmacologically active compound is metabolized by a cytochrome
P450 monooxygenase; l) the method of claim (k) wherein the
pharmacologically active compound is an antiretrovial compound; m)
the method of claim (l) wherein the antiretroviral compound is a
protease inhibitor, a nucleoside reverse transcriptase inhibitor,
or a non-nucleoside reverse transcriptase inhibitor, or a
pharmaceutically acceptable prodrug, salt, hydrate, solvate, or
polymorph thereof; n) the method of claim (m) wherein the protease
inhibitor is lopinavir, saquinavir, indinavir, nelfinavir,
amprenavir, palinavir, lasinavir, or tipranavir; o) the method of
claim (m) wherein the nucleoside reverse transcriptase inhibitor is
zidovudine, zalcitabine, lamivudine, didanosine, abacavir, tidoxil,
stavudine, adefovir, adefovir, dipivoxil, or fozivudine; p) the
method of claim (m) wherein the non-nucleoside reverse
transcriptase inhibitor is delavirdine, efavirenz, immunocal,
loviride, nevirapine, or oltipraz; q) a method of preparing a
pharmaceutical composition comprising Ritonavir, which comprises
contacting Ritonavir(III), Ritonavir(IV), or Ritonavir(V) with an
aqueous solution; or r) a method of preparing a pharmaceutical
composition comprising Ritonavir, which comprises contacting
Ritonavir (III), Ritonavir (IV), or Ritonavir (V) with an
alcohol-based solution.
4. A pharmaceutical composition comprising Ritonavir(V).
5. A single unit dosage form comprising the composition of claim
4.
6. A kit comprising a single unit dosage form of Ritonavir(V) and a
single unit dosage form of an antiviral compound.
7. The kit of claim 6 wherein the antiretroviral compound is a
protease inhibitor, a nucleoside reverse transcriptase inhibitor,
or a non-nucleoside reverse transcriptase inhibitor, or a
pharmaceutically acceptable prodrug, salt, hydrate, solvate, or
polymorph thereof.
Description
RELATED APPLICATIONS
[0001] This application claims benefit to U.S. Provisional Patent
Application No. 60/377,211 filed May 3, 2002, which is hereby
incorporated by reference.
1. FIELD OF INVENTION
[0002] This invention relates to crystal forms of Ritonavir,
methods of making and using the same, and pharmaceutical
compositions comprising the same.
2. BACKGROUND OF THE INVENTION
[0003] Many compounds can exist in different crystal forms, or
polymorphs. Individual polymorphs can exhibit different physical,
chemical, and spectroscopic properties. For example, certain
polymorphs may be more readily soluble in particular solvents, may
flow more readily, or may compress more easily than others. See,
e.g., P. DiMartino, et al., J. Thermal Anal., 48:447-458 (1997). In
the case of drugs, certain forms may be more bioavailable than
others, while others may be more stable under certain
manufacturing, storage, and biological conditions. This is
particularly important from a regulatory standpoint, since drugs
are approved by agencies such as the United States Food and Drug
Administration ("FDA") only if they meet exacting purity and
characterization standards. Indeed, the regulatory approval of one
polymorph of a compound, which exhibits certain solubility and
physico-chemical (including spectroscopic) properties, typically
does not imply the ready approval of other polymorphs of that same
compound.
[0004] One compound, which has received a lot of attention in
connection with polymorphism, is Ritonavir. Ritonavir is chemically
named
10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3-
,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic
acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,1OR*,11R*)], and has
the following structural formula: 1
[0005] Ritonavir is an inhibitor of the HIV-1 and HIV-2 proteases
with in vitro and in vivo activity against the Human
Immunodeficiency Virus ("HIV"), and is presently sold in a soft
gelatin capsule dosage form for oral administration under the trade
name NORVIR.RTM. (Abbott Laboratories, North Chicago, Ill. USA).
NORVIR.RTM. is indicated for use in combination with other
antiretroviral agents for the treatment of HIV-infection.
PHYSICIANS' DESK REFERENCE, 487-492 (56.sup.th ed., 2002). The
combination of Ritonavir and Lopinavir is sold in a capsule dosage
form for oral administration under the trade name KALETRA.TM.,
which is also indicated for use in combination with other
antiretroviral agents for the treatment of HIV-infection. Id. at
471-478.
[0006] During the development and initial manufacture of Ritonavir,
only one crystal form was identified. Bauer, J., et al., Pharm.
Res., 18(6):859-866 (2001). Because Ritonavir is not bioavailable
in that form, however, the initially marketed oral formulations
that comprised it contained Ritonavir dissolved in a semi-solid,
waxy matrix filled into capsules. About two years after the initial
marketing of NORVIR.RTM., a second crystal form of Ritonavir was
discovered; its presence in the capsule formulation caused the
product to fail the dissolution specification mandated by the
regulatory agencies. Id. As it later turned out, this new form,
which is referred to as "Form II," was supersaturated in the
hydroalcoholic solutions used in the drug formulations, even though
the originally known form, which is now referred to as "Form I,"
was not. The sudden appearance of the significantly less soluble
Form II prevented the further manufacture of the original
NORVIR.RTM. formulations, and seriously threatened the supply of
the drug. Id. At some considerable cost, a new formulation of
NORVIR.RTM. was eventually developed.
[0007] Until now, only two crystalline forms of Ritonavir--Forms I
and II--were known., Id.; Chemburkar, S. R., et al., Organic
Process Res. Dev., 4:413-417 (2000) ("Chemburkar"). Form I has a
melting point of 122.degree. C.; Form II has a melting point of
125.degree. C. Chemburkar et al.
[0008] A need exists for other crystalline forms of Ritonavir, and
bioavailable crystalline forms in particular. A need also exists
for crystalline forms of the drug that can be used to more readily
manufacture Forms I and II. Forms of Ritonavir are also desired
which, when combined with other drugs, can be used to provide
combination therapies that are more effective and/or better
tolerated than those currently in use.
[0009] HIV infection is often treated using combination therapies,
wherein two or more pharmaceutically active compounds are
administered to the patient (e.g., together as a "drug cocktail").
Current therapies for HIV infection focus on inhibiting the
activity of viral enzymes that are critical in the life cycle of
the virus, such as reverse transcriptase and protease.
Antiretrovirals that are presently in use are generally grouped
into three classes: nucleoside reverse transcriptase inhibitors
("NRTIs"); non-nucleoside reverse transcriptase inhibitors
("NNRTIs"); and protease inhibitors ("PIs"). Combination therapies
using such compounds have been shown to reduce the incidence of
opportunistic infections and to increase survival time. It is
possible that these and other benefits of combination therapies may
be further improved by the use of new crystalline forms of
Ritonavir.
3. SUMMARY OF THE INVENTION
[0010] This invention encompasses novel solvates and crystal
polymorphs of Ritonavir. Specific solvates of the compound include
a formamide solvate and a partially desolvated formamide solvate.
All of the novel forms exhibit physical and spectroscopic
characteristics that differ markedly from those of Forms I and
II.
[0011] The invention further encompasses methods of making novel
forms of Ritonavir, as well as methods of making previously known
forms. Also encompassed by the invention are methods of using the
novel forms of Ritonavir in the treatment of diseases, such as
HIV-infection, and for enhancing the pharmacokinetic profiles of
other pharmaceutically active compounds. Pharmaceutical
compositions and unit dosage forms comprising novel forms of
Ritonavir are also encompassed by the invention.
3.1. BRIEF DESCRIPTION OF THE FIGURES
[0012] Aspects of the invention can be understood with reference to
the following non-limiting figures:
[0013] FIG. 1 is a Raman spectrum of Ritonavir Form I in the solid
state.
[0014] FIG. 2A is a powder X-ray diffraction pattern of Ritonavir
Form I, and FIG. 2B contains a peak table for that diffraction
pattern.
[0015] FIG. 3 contains a Raman spectrum of Ritonavir Form II in the
solid state.
[0016] FIG. 4A is a powder X-ray diffraction pattern of Ritonavir
Form II, and FIG. 4B contains a peak table for that diffraction
pattern.
[0017] FIG. 5 is a DSC trace of Ritonavir Form III.
[0018] FIG. 6 is a TGA trace of Ritonavir Form III.
[0019] FIG. 7 is a Raman spectrum of Ritonavir Form III in the
solid state.
[0020] FIG. 8A is a powder X-ray diffraction pattern of Ritonavir
Form III, and FIG. 8B contains a peak table for that diffraction
pattern.
[0021] FIG. 9 is a DSC trace of Ritonavir Form IV.
[0022] FIG. 10 is a TGA trace of Ritonavir Form IV.
[0023] FIG. 11 is a Raman spectrum of Ritonavir Form IV in the
solid state.
[0024] FIG. 12A is a powder X-ray diffraction pattern of Ritonavir
Form IV, and FIG. 12B contains a peak table for that diffraction
pattern.
[0025] FIG. 13 is a DSC trace of Ritonavir Form V.
[0026] FIG. 14 is a TGA trace of Ritonavir Form V.
[0027] FIG. 15 is a Raman spectrum of Ritonavir Form V in the solid
state.
[0028] FIG. 16A is a powder X-ray diffraction pattern of Ritonavir
Form V, and FIG. 16B contains a peak table for that diffraction
pattern.
[0029] FIG. 17 shows, by DSC trace, the conversion of Ritonavir
Form III to Form IV, and subsequently to Form I while being washed
or incubated in aqueous media.
[0030] FIG. 18 provides a comparison of powder X-ray diffraction
patterns of Ritonavir Forms I, II, III, IV, and V.
[0031] FIG. 19 shows the effect of leaving Ritonavir Form V in the
crystallization mixture for about 16 hours at 5.degree. C. In
particular: (A) is a representative X-ray diffraction pattern of
Ritonavir(I); (B) is an X-ray diffraction pattern of a sample of
Ritonavir(V) after being left in the crystallization mixture for
approximately 16 hours, with arrows indicating peaks that signify
the presence of Ritonavir(I); and (C) is a representative X-ray
diffraction pattern of Ritonavir(V).
[0032] FIG. 20 also shows the effect of leaving Ritonavir Form V in
the crystallization mixture for about 16 hours at 5.degree. C. In
particular: (A) provides a DSC trace of Ritonavir(I); (B) provides
a DSC trace of a sample of Ritonavir(V) after being left in the
crystallization mixture for approximately 16 hours, wherein two
peaks are observed corresponding to Forms I and V; and (C) is a
representative DSC trace of Ritonavir(V).
4. DETAILED DESCRIPTION OF THE INVENTION
[0033] This invention is based, in part, on a discovery that the
protease inhibitor ("PI") Ritonavir can be obtained in novel
crystalline forms. Advantageously, these new forms have lower
melting points than previously known forms of Ritonavir (i.e.,
Forms I and II), which have poor bioavailability, and may thus be
used to provide improved dissolution of Ritonavir. Forms of this
invention may also be used to enhance the pharmacokinetics of other
drugs (e.g., retroviral agents and reverse transcriptase
inhibitors). The new forms of Ritonavir may also be used as
intermediates in the manufacture of Forms I and II, as well as in
the manufacture of pharmaceutical compositions and dosage forms
comprising Ritonavir (e.g., dosage forms comprising dissolved
Ritonavir). A further advantage of this invention is that methods
of preparing the novel forms disclosed herein can be used to
prepare those forms on a variety of scales, from microgram to
milligram, gram, and even kilogram quantities.
[0034] A first embodiment of the invention encompasses what is
referred to herein as "Ritonavir Form III" or "Ritonavir(III)."
Ritonavir(III) has a melting point in the range of from about
78.degree. C. to about 82.degree. C., as exemplified by the
Differential Scanning Calorimetry ("DSC") trace of the form shown
in FIG. 5, which shows a melting point of about 79.degree. C. A
typical Thermal Gravimetric Analysis ("TGA") trace of
Ritonavir(III) is provided in FIG. 6. Typical Raman spectra and
powder X-ray diffraction patterns of Ritonavir(III) are provided in
FIGS. 7 and 8, respectively. Without being limited by theory, it is
believed that Ritonavir(III) is a formamide solvate of
Ritonavir.
[0035] Another embodiment of the invention encompasses what is
referred to herein as "Ritonavir Form IV" or "Ritonavir(IV)."
Ritonavir(IV) has a melting point in the range of from about
97.degree. C. to about 101.degree. C., as exemplified by the DSC
trace of the form shown in FIG. 9, which shows a melting point of
about 101.degree. C. A typical TGA trace of Ritonavir(IV) is
provided in FIG. 10. Typical Raman spectra and powder X-ray
diffraction patterns of Ritonavir(IV) are provided in FIGS. 11 and
12, respectively. Without being limited by theory, it is believed
that Ritonavir(IV) is a partially desolvated formamide solvate of
Ritonavir.
[0036] Another embodiment of the invention encompasses what is
referred to herein as "Ritonavir Form V" or "Ritonavir(V)."
Ritonavir(V) has a melting point in the range of from about
114.degree. C. to about 118.degree. C., as exemplified by the DSC
spectrum of the form shown in FIG. 13, which shows a melting point
of about 116.degree. C. A typical TGA trace of Ritonavir(V) is
provided in FIG. 14. Typical Raman and powder X-ray diffraction
spectra of Ritonavir(V) are provided in FIGS. 15 and 16,
respectively. Without being limited by theory, it is believed that
Ritonavir(V) is a polymorph of Ritonavir Forms I and II.
[0037] Another embodiment of the invention encompasses a method of
making Ritonavir(III), which comprises dissolving Ritonavir in a
solvent system comprised of formamide and an immiscible or
partially miscible solvent to provide a mixture, and reducing the
solubility of Ritonavir in the mixture under conditions sufficient
to provide Ritonavir(III). A specific solvent system is a binary
solvent system. Preferred immiscible or partially miscible solvents
include, but are not limited to, toluene, butyl acetate, and
acetone. In a specific method, the solubility of Ritonavir(III) is
reduced by cooling the mixture. In another method, the solubility
of Ritonavir(III) is reduced by evaporating some of the mixture. In
any of these methods, Ritonavir(III) can be crystallized from
static layers of the solvents, or while the solvents are vigorously
stirred (e.g., with a non-reactive magnetic stirrer).
[0038] Another embodiment of the invention encompasses a method of
making Ritonavir(IV), which comprises partially desolvating
Ritonavir(III) to an extent sufficient to yield Ritonavir(IV). In a
specific method, Ritonavir(III) is contacted with an aqueous medium
in an amount and for a time sufficient to form Ritonavir(IV).
[0039] Another embodiment of the invention encompasses a method of
making Ritonavir(V), which comprises drying Ritonavir(III) in a
vacuum in an amount and for a time sufficient to form
Ritonavir(IV). In a specific method, Ritonavir(III) is placed in a
vacuum oven to dry for about 38 hours.
[0040] Another embodiment of the invention encompasses a method of
making Ritonavir(V), which comprises dissolving Ritonavir in a
solvent system comprised of an acetate (e.g., an alkyl acetate) and
acetonitrile to produce a mixture, and reducing the solubility of
Ritonavir in the mixture under conditions sufficient to provide
Ritonavir(V). A specific solvent system is a binary solvent system.
Specific acetates include, but are not limited to, butyl acetate,
isobutyl acetate, and isopropyl acetate. A preferred ratio of
acetate to acetonitrile is from about 50:50 to about 75:25
acetate:acetonitrile. In a specific method, the solubility of
Ritonavir(V) is reduced by cooling the mixture. In another method,
the solubility of Ritonavir(V) is reduced by partially evaporating
solvent from the mixture.
[0041] Another embodiment of the invention encompasses a method of
treating, ameliorating, or managing a disease or condition
associated with the proteolytic activity of HIV protease, which
comprises administering to a patient in need of such treatment or
prevention a therapeutically or prophylactically effective amount
of Ritonavir(III), Ritonavir(IV), or Ritonavir(V). Preferred
methods comprise the administration of Ritonavir(V).
[0042] Another embodiment of the invention encompasses a method for
improving the pharmacokinetics' of a pharmacologically active
compound, which comprises administering to a human in need of the
pharmacologically active compound a combination of a
therapeutically effective amount of Ritonavir(III), (IV), or (V),
or a pharmaceutically acceptable salt thereof, and a
therapeutically effective amount of the pharmacologically active
compound, or a pharmaceutically acceptable prodrug, salt, hydrate,
solvate, or polymorph thereof, wherein the pharmacologically active
compound is metabolized by cytochrome P450 monooxygenase(s). In a
particular embodiment, the pharmacologically active compound is an
antiretroviral compound. Examples of antiretroviral compounds
include, but are not limited to, PIs, NRTIs, and NNRTIs.
[0043] Another embodiment of the invention encompasses
pharmaceutical compositions and dosage forms of Ritonavir(III),
Ritonavir(IV), and Ritonavir(V). Preferred compositions and dosage
forms comprise Ritonavir(V), optionally in combination with another
pharmacologically active compound (e.g., a second HIV protease
inhibitor or one or more HIV reverse transcriptase inhibitors).
[0044] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, derivatives of pharmacologically active
compounds that include biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides,
and biohydrolyzable phosphate analogues. Prodrugs can typically be
prepared using well-known methods, such as those described in 1
BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY, 172-178, 949-982
(Manfred E. Wolff ed., 5.sup.th ed. 1995), and DESIGN OF PRODRUGS
(H. Bundgaard ed., Elselvier, N.Y. 1985).
[0045] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide,"
"biohydrolyzable phosphate" mean an amide, ester, carbamate,
carbonate, ureide, or phosphate, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, lower
acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,
aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl
esters), lactonyl esters (such as phthalidyl and thiophthalidyl
esters), lower alkoxyacyloxyalkyl esters (such as
methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and
isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline
esters, and acylamino alkyl esters (such as acetamidomethyl
esters). Examples of biohydrolyzable amides include, but are not
limited to, lower alkyl amides, a-amino acid amides, alkoxyacyl
amides, and alkylaminoalkylcarbonyl amides. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0046] As used herein and unless otherwise indicated, the term
"pharmaceutically acceptable salts" refer to salts prepared from
pharmaceutically acceptable non-toxic acids or bases including
inorganic acids and bases and organic acids and bases. Suitable
pharmaceutically acceptable base addition salts for the compound of
the present invention include metallic salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc or organic
salts made from lysine, N,N*-dibenzylethylenediamine,
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Suitable non-toxic acids include,
but are not limited to, inorganic and organic acids such as acetic,
alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic,
citric, ethenesulfonic, fornmic, fumaric, furoic, galacturonic,
gluconic, glucuronic, glutamic, glycolic, hydrobromic,
hydrochloric, isethionic, lactic, maleic, malic, mandelic,
methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,
phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,
sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific
non-toxic acids include hydrochloric, hydrobromic, phosphoric,
sulfuric, and methanesulfonic acids. Examples of specific salts
thus include hydrochloride and mesylate salts.
4.1. PREPARATION OF SOLVATES AND POLYMORPHS
[0047] This invention evidences the power and utility of the
methods and systems collectively referred to as CRYSTALMAX.TM.,
which are described in U.S. provisional patent application No.
60/221,539, filed Jul. 28, 2000; U.S. patent application Ser. No.
09/756,092, filed Jan. 8, 2001; International Publication
WO01/51919; U.S. provisional patent application No. 60/318,157,
filed Sep. 7, 2001; U.S. provisional patent application No.
60/318,138, filed Sep. 7, 2001; U.S. provisional patent application
No. 60/318,152, filed Sep. 7, 2001; and U.S. provisional patent
application No. 60/366,523, filed Mar. 22, 2002, all of which are
incorporated herein by reference.
[0048] Using the CRYSTALMAX.TM. methods and systems, it was
discovered that Ritonavir(III) can be crystallized from solvent
systems (e.g., binary systems) comprised of formamide and an
immiscible or partially miscible solvent. In particular, it was
discovered that after Ritonavir is dissolved in such a solvent
system at an elevated temperature (e.g., about 70.degree. C.), the
slow cooling of the resulting mixtures (e.g., at a rate of about
5.degree. C./minute until a temperature of about 5.degree. C. is
reached) typically yields crystals of Ritonavir(III), which can be
isolated by filtration and optionally dried by air. Specific
immiscible or partially miscible solvents include, but are not
limited to, toluene, butyl acetate, and acetone. Specific solvent
systems comprise about 75 volume percent form amide.
[0049] Ritonavir(IV) can be prepared from Ritonavir(III). In a
particular method, Ritonavir(III) is contacted with an aqueous
medium for an amount of time sufficient to effect the change. For
example, Ritonavir(III) placed on a vacuum filter can be washed
with deionized water, thereby providing Ritonavir(IV). When
Ritonavir(IV) is exposed to an aqueous environment for an extended
amount of time (e.g., about 15 to about 60 minutes), it converts to
Ritonavir Form I. Prolonged exposure of Ritonavir(IV) to an aqueous
environment converts the compound to Ritonavir Form II.
[0050] Ritonavir(V) is readily prepared from solvent systems (e.g.,
binary solvent systems) comprised of an acetate and acetonitrile.
In particular, it was discovered that after Ritonavir is dissolved
in such a solvent system at an elevated temperature (e.g., about
70.degree. C.), the slow cooling of the resulting mixtures (e.g.,
at a rate of about 5.degree. C./minute until a temperature of about
5.degree. C. is reached) typically yields crystals of Ritonavir(V),
which can be isolated by filtration and optionally dried by air.
Specific solvent systems comprise from about 25 to about 50 volume
percent acetonitrile. It was also found that prolonged incubation
of Ritonavir(V) in the crystallization mixture provides Ritonavir
Form I.
4.2. METHODS OF TREATMENT AND PREVENTION
[0051] Compounds of the invention (e.g., Ritonavir(V)) can be used
for the treatment or management of diseases and conditions
associated with activity of HIV proteases. Examples of such
diseases and conditions include, but are not limited to,
HIV-infection.
[0052] As discussed herein, compounds of the invention are
typically incorporated into pharmaceutical compositions, such as
individual dosage forms suitable for administration by any of a
variety of routes. The magnitude of a prophylactic or therapeutic
dose of a pharmaceutical composition of the invention for the acute
or chronic management of a disease will vary with the severity of
the condition to be treated and the route of administration. The
dose, and perhaps the dose frequency, will also vary according to
age, body weight, response, and the past medical history of the
individual patient. For example, the general recommended daily dose
range for the treatment and/or prevention of the diseases,
disorders, and/or conditions described herein using a
pharmaceutical composition comprising Ritonavir as the active
ingredient lie within the range of from about 100 mg to about 1200
mg, from 200 mg to about 1000 mg, and from 400 mg to about 800 mg
twice daily by mouth. A preferred dose is about 600 mg Ritonavir
twice daily. Dose titration schedules such as those published in
connection with NORVIR.RTM. may be used to reduce or avoid adverse
effects. See, e.g., PHYSICIANS' DESK REFERENCE, 487-492 (56.sup.th
ed., 2002).
[0053] As with previously known forms of Ritonavir, those of the
invention can be combined or adjunctively administered with other
pharmacologically active compounds when used to treat or prevent
diseases or conditions. For example, compounds of the invention can
be administered in combination with other compounds or
pharmaceutical agents for the treatment or prevention of infectious
disease of HIV including, but not limited to, PIs, NRTIs, and
NNRTIs. Examples of PIs include, but are not limited to, lopinavir,
saquinavir, indinavir, nelfinavir, amprenavir, palinavir,
lasinavir, tipranavir, and those disclosed in U.S. Pat. Nos.
6,284,767; 5,886,036; 5,846,987; and 5,635,523, all of which are
incorporated herein by reference. Examples of NRTIs include, but
are not limited to, zidovudine, zalcitabine, lamivudine,
didanosine, abacavir, tidoxil, stavudine, adefovir, adefovir
dipivoxil, fozivudine, and the like. Examples of NNRTIs (which may
also include an agent having antioxidation activity) include, but
are not limited to, delavirdine, efavirenz, immunocal, loviride,
nevirapine, oltipraz, and the like.
[0054] Ritonavir reportedly inhibits, and is believed to be
metabolized by, isoforms of cytochrome P450 monooxygenase,
including without limitation CYP3A and CYP2D6. See, U.S. Pat. No.
6,037,157 and PHYSICIANS' DESK REFERENCE, 487-492 (56.sup.th ed.,
2002). Consequently, when Ritonavir is co-administered with a
second compound or pharmaceutical that is metabolized by one or
more cytochrome P450 monooxygenases inhibited by Ritonavir, the
pharmacokinetics of the second compound may be affected. For
example, the clearance of the second compound may be slowed, and
its blood level thereby increased. See, e.g., PHYSICIANS' DESK
REFERENCE, 488-9, Tables 2 and 4 (56.sup.th ed., 2002). Because of
its ability to affect the metabolism of other drugs (e.g.,
antiviral drugs), Ritonavir can be used to provide combination
therapies that are particularly advantageous. In particular,
Ritonavir can increase the pharmacological activity of a
co-administered compound, allowing a reduction of its dose. The
co-administration of Ritonavir may also increase the blood
half-life of a co-administered compound such that its
administration need not be as frequent or may occur by a different
route (e.g., oral, instead of intravenous), thereby enhancing
patient compliance. Ritonavir administration may also be used to
improve the safety profile of the co-administered compound, as less
of that compound may be needed to elicit its desired
pharmacological (e.g., antiviral) effect.
[0055] Examples of drugs which are metabolized by cytochrome P450
monooxygenase(s) and which may benefit from the co-administration
of the novel forms of Ritonavir disclosed herein include, but are
not limited to, immunosuppressants, chemotherapeutic agents,
antibiotics, antifungals, and HIV protease inhibitors. Examples of
each include, but are not limited to, those disclosed in U.S. Pat.
No. 6,037,157, the entirety of which is incorporated herein by
reference. Because of the unique characteristics of the Ritonavir
forms of this invention, their combination with other drugs may be
used to provide drug cocktails that are uniquely safe and
effective.
[0056] As the skilled clinician will readily recognize, the dose of
Ritonavir, and perhaps the dosing regimen used for the treatment of
a particular disease or condition with it, will likely be different
when Ritonavir is used alone or in combination with other drugs.
Guidance in connection with doses and dosing regimens may be
obtained from clinical study data and packaging information
available for previous forms of Ritonavir. See, e.g., PHYSICIANS'
DESK REFERENCE, 487-492 (56.sup.th ed., 2002).
[0057] The term "therapeutically or prophylactically effective
amount" when used to describe a method of the invention (e.g., a
method of treating HIV-infection) encompasses the above described
dosage amounts and dose frequency schedules.
[0058] Methods of the invention that are directed to the
prevention, amelioration, or management of a disease, disorder, or
condition comprise the administration of a form of Ritonavir to a
patient at risk of suffering from the disease, disorder, or
condition. In general, a qualified physician will readily be able
to determine whether or not a given patient is at risk. For
example, those of ordinary skill in the art are well aware of
patient populations at risk of HIV-infection.
[0059] Any suitable route of administration can be employed to
provide the patient with a therapeutically or prophylactically
effective dose of an active ingredient. For example, oral, mucosal
(e.g., nasal, sublingual, buccal, rectal, vaginal), parenteral
(e.g., intravenous, intramuscular), transdermal, and subcutaneous
routes can be employed. A preferred route of administration is
oral.
4.3. PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
[0060] Pharmaceutical compositions and dosage forms of the
invention comprise a compound of the invention (e.g.,
Ritonavir(V)), typically in combination with one or more
pharmaceutically acceptable excipients, and optionally in
combination with one or more additional pharmacologically active
compounds. Examples of additional pharmacologically active
compounds include, but are not limited to, PIs, NRTIs, and NNRTIs,
such as those disclosed herein. Other additional pharmacologically
active compounds include, but are not limited to,
immunosuppressants, chemotherapeutic agents, antifungals, and
antibiotics.
[0061] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), or transdermal
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as hard
gelatin, HPMC, starch, and soft elastic gelatin capsules; cachets;
troches; lozenges; dispersions; suppositories; ointments;
cataplasms (poultices); pastes; powders; dressings; creams;
plasters; solutions; patches; aerosols (e.g., nasal sprays or
inhalers); gels; liquid dosage forms suitable for oral or mucosal
administration to a patient, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil-in-water emulsions, or a
water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
and sterile solids (e.g., crystalline or amorphous solids) that can
be reconstituted to provide liquid dosage forms suitable for
parenteral administration to a patient.
[0062] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form suitable for mucosal administration may contain a
smaller amount of active ingredient(s) than an oral dosage form
used to treat the same indication. This aspect of the invention
will be readily apparent to those skilled in the art. See, e.g.,
REMINGTON'S PHARMACEUTICAL SCIENCES, 18.sup.th ed., Mack
Publishing, Easton Pa. (1990).
[0063] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form. For example, the decomposition of some active
ingredients can be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary
or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, this invention encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose or other mono- or di-saccharides. As used herein,
the term "lactose-free" means that the amount of lactose present,
if any, is insufficient to substantially increase the degradation
rate of an active ingredient.
[0064] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,
lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0065] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. Water and heat accelerate the
decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0066] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0067] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials) with or without
dessicants, blister packs, and strip packs.
[0068] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0069] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise Ritonavir in an amount of from
about 50 mg to about 1000 mg, preferably in an amount of from about
75 mg to about 750 mg, and most preferably in an amount of from
about 100 mg to about 500 mg.
4.4.1. ORAL DOSAGE FORMS
[0070] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, REMINGTON'S
PHARMACEUTICAL SCIENCES, 18.sup.th ed., Mack Publishing, Easton Pa.
(1990).
[0071] Typical oral dosage forms of the invention are prepared by
combining the active ingredient(s) in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, stabilizers, and
disintegrating agents.
[0072] Because of their ease of administration, tablets, caplets,
and capsules represent the most advantageous oral dosage unit
forms, in which case solid excipients are employed. If desired,
tablets and caplets can be coated by standard aqueous or nonaqueous
techniques. Such dosage forms can be prepared by any of the methods
of pharmacy. In general, pharmaceutical compositions and dosage
forms are prepared by uniformly and intimately admixing the active
ingredients with liquid carriers, finely divided solid carriers, or
both, and then shaping the product into the desired presentation if
necessary.
[0073] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0074] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
stabilizers, disintegrants, surfactants (as wetting agents) and
lubricants. Binders suitable for use in pharmaceutical compositions
and dosage forms include, but are not limited to, corn starch,
potato starch, or other starches, gelatin, natural and synthetic
gums such as acacia, sodium alginate, alginic acid, other
alginates, powdered tragacanth, guar gum, cellulose and its
derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0075] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. A specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0076] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0077] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0078] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0079] Examples of surfactants as wetting agents or aids include,
but are not limited to, sodium lauryl sulfate (SDS) and poloxamers
(e.g., PLURONICS). The former is a solid while the latter are
liquids and available in various grades (ex. 188, 237, etc.) based
on molecular weight. The action of these agents in pharmacuetical
compositions or formulation is particularly important as the oral
dosage forms are ingested and drug release must take place in the
body.
[0080] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0081] Specific dosage forms into which Ritonavir(III),
Ritonavir(IV), and Ritonavir(V) can be incorporated, or which can
be prepared using the forms of this invention, are disclosed in
U.S. Pat. No. 6,232,333, which is incorporated herein by
reference.
4.4.2. DELAYED RELEASE DOSAGE FORMS
[0082] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos.: 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example, hydroxypropyl
methyl cellulose, other polymer matrices, gels, permeable
membranes, osmotic systems, multilayer coatings, microparticles,
liposomes, microspheres, or a combination thereof to provide the
desired release profile in varying proportions. Suitable
controlled-release formulations known to those of ordinary skill in
the art, including those described herein, can be readily selected
for use with the active ingredients of the invention. The invention
thus encompasses single unit dosage forms suitable for oral
administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0083] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0084] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
4.4.3. PARENTERAL DOSAGE FORMS
[0085] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0086] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and propylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0087] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention.
4.4.4. TRANSDERMAL, TOPICAL, AND MUCOSAL DOSAGE FORMS
[0088] Transdermal, topical, and mucosal dosage forms of the
invention include, but are not limited to, ophthalmic solutions,
sprays, aerosols, creams, lotions, ointments, gels, solutions,
emulsions, suspensions, or other forms known to one of skill in the
art. See, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES, 16.sup.th and
18.sup.th eds., Mack Publishing, Easton Pa. (1980 & 1990); and
INTRODUCTION TO PHARMACEUTICAL DOSAGE FORMS, .sub.4.sup.th ed., Lea
& Febiger, Philadelphia (1985). Dosage forms suitable for
treating mucosal tissues within the oral cavity can be formulated
as mouthwashes or as oral gels. Further, transdermal dosage forms
include "reservoir type" or "matrix type" patches, which can be
applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active
ingredients.
[0089] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide transdermal, topical, and
mucosal dosage forms encompassed by this invention are well known
to those skilled in the pharmaceutical arts, and depend on the
particular tissue to which a given pharmaceutical composition or
dosage form will be applied. With that fact in mind, typical
excipients include, but are not limited to, water, acetone,
ethanol, ethylene glycol, propylene glycol, butane-1,3-diol,
isopropyl myristate, isopropyl palmitate, mineral oil, and mixtures
thereof to form lotions, tinctures, creams, emulsions, gels or
ointments, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms if desired. Examples of such
additional ingredients are well known in the art. See, e.g.,
REMINGTON'S PHARMACEUTICAL SCIENCES, 16.sup.th and 18.sup.th eds.,
Mack Publishing, Easton Pa. (1980 & 1990).
[0090] Depending on the specific tissue to be treated, additional
components may be used prior to, in conjunction with, or subsequent
to treatment with active ingredients of the invention. For example,
penetration enhancers can be used to assist in delivering the
active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as
ethanol, oleyl, and tetrahydrofuryl; alkyl sulfoxides such as
dimethyl sulfoxide; dimethyl acetamide; dimethyl formamide;
polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various
water-soluble or insoluble sugar esters such as Tween 80
(polysorbate 80) and Span 60 (sorbitan monostearate).
[0091] The pH of a pharmaceutical composition or dosage.form, or of
the tissue to which the pharmaceutical composition or dosage form
is applied, may also be adjusted to improve delivery of one or more
active ingredients. Similarly, the polarity of a solvent carrier,
its ionic strength, or tonicity can be adjusted to improve
delivery. Compounds such as stearates can also be added to
pharmaceutical compositions or dosage forms to advantageously alter
the hydrophilicity or lipophilicity of one or more active
ingredients so as to improve delivery. In this regard, stearates
can serve as a lipid vehicle for the formulation, as an emulsifying
agent or surfactant, and as a delivery-enhancing or
penetration-enhancing agent. Different salts, hydrates or solvates
of the active ingredients can be used to further adjust the
properties of the resulting composition.
4.4.5. KITS
[0092] Typically, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0093] A typical kit of the invention comprises a unit dosage form
of Ritonavir(V) and a unit dosage form of a second
pharmacologically active compound, such as an HIV protease
inhibitor. A kit may further comprise a device that can be used to
administer the active ingredient. Examples of such devices include,
but are not limited to, syringes, drip bags, patches, and
inhalers.
[0094] Kits of the invention can further comprise pharmaceutically
acceptable vehicles that can be used to administer one or more
active ingredients. For example, if an active ingredient is
provided in a solid form that must be reconstituted for parenteral
administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to
form a particulate-free sterile solution that is suitable for
parenteral administration. Examples of pharmaceutically acceptable
vehicles include, but are not limited to: Water for Injection USP;
aqueous vehicles such as, but not limited to, Sodium Chloride
Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection;
water-miscible vehicles such as, but not limited to, ethyl alcohol,
polyethylene glycol, and propylene glycol; and non-aqueous vehicles
such as, but not limited to, corn oil, cottonseed oil, peanut oil,
sesame oil, ethyl oleate, isopropyl myristate, and benzyl
benzoate.
5. EXAMPLES
[0095] Certain aspects and embodiments of the invention are
illustrated by the following non-limiting examples.
5.1. EXAMPLE 1
[0096] Preparation of Ritonavir Form I
[0097] NORVIR-brand Ritonavir (Abbott Laboratories, North Chicago,
Ill. USA) oral solution was used to obtain Ritonavir Form I.
Specifically, approximately 240 mL of NORVIR solution (the contents
of a normal prescription bottle, totaling about 19.2 g of
Ritonavir) were placed into a 500 mL round bottom flask and
vacuum-treated (pumping at high vacuum) for about 6 hours at room
temperature on a slightly heated water bath to keep temperature
constant. 50 mL of ethyl acetate was added to the viscous residue
(dark orange in color).
[0098] The resulting solution was placed into a 2 liter flask and
while stirring, diethyl ether was added to a final volume of about
1800 mL. The solution was stirred for 30 minutes at room
temperature to allow precipitation to occur. The ether phase was
poured through a 150 mL sintered glass, coarse frit funnel to
clarify the ether. Successive aliquots of approx. 300 mL of
filtrate were placed into a 500 mL round bottom flask and the
solvent was removed by rotary evaporation in vacuo (water
aspirator) until a slightly off-white residue remained.
[0099] Ether aliquots were added to the residue in the round bottom
flask until all the ether had been evaporated. The final residue
was transferred into a 500 mL Erlenmeyer flask and diluted with
methylene chloride to a final volume of about 150 mL. A total of
about 350 mL deionized water was added to the methylene chloride
solution by gently pouring down the edge of the flask, while the
solution was stirred by a magnetic stirbar on a stirplate at
approximately 200 rpm.
[0100] After about 1.5 hours of stirring, the mixture was poured
into a separatory funnel. After settling, the methylene chloride
fraction (bottom layer) was separated into an Erlenmeyer flask, and
allowed to dry over anhydrous sodium sulfate for 15 minutes (during
which time the organic solvent went from opaque to clear).
[0101] After filtering the methylene chloride solution, the solvent
was removed by rotary evaporation. The resulting residual syrup was
placed in a -20.degree. C. freezer overnight to allow crystals to
form. The crystals were isolated, and then the solid compound was
dissolved in approximately 350 mL of ethyl acetate at about
44.degree. C. Approximately 175 mL of hexane was added with
stirring until product began to precipitate.
[0102] A sealed vial containing the mixture was placed in a
refrigerator at 4.degree. C. overnight to crystallize.
Recrystallization in ethyl acetate/hexane was repeated once more to
give the final product, which was dried in vacuo for about 12
hours.
[0103] The identity of the sample as Ritonavir Form I was
established by powder X-ray diffraction (distinguishing peaks at
3.3, 6.8, 8.4, and 21.6 2-theta) and purity by elemental analysis
(Calcd. %--C: 61.66, H: 6.66, N: 11.66; Obsd. %--C: 61.74, H: 6.78,
N: 11.41).
5.2. EXAMPLE 2
[0104] Preparation of Ritonavir(III)
[0105] In order to prepare Ritonavir(III), 10 mg of Ritonavir Form
I obtained in Example 1 above, 37.5 .mu.L of formamide, and 12.5
.mu.L of toluene (50 .mu.L solvent total, containing 75% formamide)
were deposited into a crimp-top 200 .mu.L capacity glass vial. The
vial was sealed with a crimp top and subsequently incubated at
70.degree. C. until the Ritonavir solid dissolved. The vial was
then cooled at a rate of approximately 5.degree. C./minute to
5.degree. C. The vial was incubated at 5.degree. C. until crystals
were observed. The crystals in the vial were removed from the
supernatant by filtration, air dried, and characterized as
described herein.
[0106] Ritonavir(III) was also prepared using the same process
conditions from the following mixtures: 10 mg of Ritonavir Form I,
37.5 .mu.L of formamide, and 12.5 .mu.L of butyl acetate; and 10 mg
of Ritonavir Form I, 37.5 .mu.L of formamide, and 12.5 .mu.L of
acetone.
5.3. EXAMPLE 3
[0107] Preparation of Ritonavir(IV)
[0108] 50 mg of Ritonavir(III) obtained in Example 2 above was
placed on filter paper in a Buchner funnel, which was fitted to a
vacuum flask connected to an aspirator. With the vacuum on, 10 mL
of deionized water was slowly poured over the solid Ritonavir(III).
The resulting material on the filter was dried over vacuum for
approximately 15 minutes, and characterized as described
herein.
5.4. EXAMPLE 4
[0109] Preparation of Ritonavir(V)
[0110] 10 mg of Ritonavir Form I obtained in Example 1 above, 37.5
.mu.L of butyl acetate, and 12.5 .mu.L of acetonitrile (50 .mu.L
solvent total, containing 25% acetonitrile) were deposited into a
crimp-top 200 .mu.L capacity glass vial. The vial was sealed with a
crimp top and subsequently incubated at 70.degree. C. until the
Ritonavir solid dissolved. The vial was then cooled at a rate of
approximately 5.degree. C./minute to 5.degree. C. The vial was
incubated at 5.degree. C. until crystals were observed. The
crystals in the vial were removed from the supernatant by
filtration, and were subsequently air dried, and characterized as
described herein.
[0111] Ritonavir(V) was also prepared using the same conditions
from the following mixtures: 10 mg of Ritonavir Form I, 25 .mu.L of
isobutyl acetate, and 25 .mu.L of acetonitrile; and 10 mg of
Ritonavir Form I, 25 .mu.L of isopropyl acetate, and 25 .mu.L of
acetonitrile.
5.5. EXAMPLE 5
[0112] Characterization of Ritonavir Solid Forms
[0113] Each of the novel forms of Ritonavir was characterized by
DSC, TGA, Raman spectroscopy, and powder X-ray diffraction
spectroscopy. As discussed below, the data obtained using these
methods make it clear that each of the forms is distinct from Forms
I and II.
5.5.1. INSTRUMENTATION
[0114] DSC data were collected for each of the forms using a Q1000
Differential Scanning Calorimeter (TA Instruments, 109 Lukens
Drive, New Castle, DE 19720), which uses as its control software
Advantage for QW-Series, version 1.0.0.78, Thermal Advantage
Release 2.0, .RTM. 2001 (TA instruments--Waters LLC). An aliquot of
the sample was weighed into an aluminum sample pan (Pan part #
900786.091; lid part # 900779.901; TA Instruments, 109 Lukens
Drive, New Castle, Del. 19720). The sample pan was sealed by press
fitting the lid. The sample pan was loaded into the apparatus,
which is equipped with an autosampler, and a thermogram was
obtained by individually heating the sample at a rate of 10.degree.
C./min from T.sub.min (typically 20.degree. C.) to T.sub.max
(typically 300.degree. C.) using an empty aluminum pan as a
reference. Dry nitrogen was used as sample purge gas at a flow rate
of 50 ml/min (compressed nitrogen, grade 4.8, BOC Gases, 575
Mountain Avenue, Murray Hill, N.J. 07974-2082). Thermal transitions
were viewed and analyzed using the analysis software Universal
Analysis. 2000 for Windows 95/95/2000/NT, version 3.1 E; Build
3.1.0.40, .RTM.1991-2001 (TA instruments--Waters LLC), provided
with the instrument.
[0115] TGA data were collected for each of the forms using a Q500
Thermogravimetric Analyzer (TA Instruments, 109 Lukens Drive, New
Castle, Del. 19720), which uses as its control software Advantage
for QW-Series, version 1.0.0.78, Thermal Advantage Release 2.0,
.RTM. 2001 (TA instruments--Waters LLC). An aliquot of the sample
was transferred into a platinum sample pan (Pan part # 952019.906;
TA Instruments, 109 Lukens Drive, New Castle, Del. 19720). The pan
was placed on the loading platform and was then automatically
loaded in to the apparatus using the control software. Thermograms
were typically obtained by individually heating the sample at
10.degree. C./min from 25.degree. C. to 300.degree. C. under
flowing dry nitrogen (compressed nitrogen, grade 4.8, BOC Gases,
575 Mountain Avenue, Murray Hill, N.J. 07974-2082), with a sample
purge flow rate of 60 ml/min and a balance purge flow rate of 40
ml/min. Thermal transitions (weight changes) were viewed and
analyzed using the analysis software Universal Analysis 2000 for
Windows 95/95/2000/NT, version 3.1E; Build 3.1.0.40, .RTM.
1991-2001 (TA instruments--Waters LLC), provided with the
instrument.
[0116] Raman data were collected for each of the novel forms of
this invention, as well as for Forms I and II, using a Nicolet
Almega.TM. Dispersive Raman system fitted with a 785 nm laser
source and controlled by the Omnic for Almega software v. 5.2a. The
sample was either left in the glass vial in which it was processed
or an aliquot of the sample was transferred to a glass slide. The
glass vial or slide was positioned in the sample chamber. The
sample was manually brought into focus using the microscope portion
of the apparatus with a 10.times. power objective (unless otherwise
noted), thus directing the laser onto the surface of the sample.
Spectra were collected in the 3250 to 105 cm.sup.-1 range, using a
100 .mu.m pin-hole aperture and sixteen, 2-second exposures. The
resulting spectra were displayed using the control software.
[0117] Powder X-ray diffraction patterns were collected for each of
the novel forms of this invention, as well as for Forms I and II.
All X-ray powder diffraction patterns were obtained using the D/Max
Rapid X-ray Diffractometer (D/Max Rapid, Rigaku/MSC, 9009 New
Trails Drive, The Woodlands, Tex., USA 77381-5209), controlled by
the RINT Rapid Control Software (Rigaku Rapid/XRD, version 1.0.0,
.RTM. 1999 Rigaku Co.) and equipped with a copper source
(Cu/K.sub..alpha.=1.5406A), manual x-y stage, and 0.3 mm
collimator. The sample was loaded into a 0.3 mm boron rich glass
capillary tube (Charles Supper Company, 15 Tech Circle, Natick
Mass. 01760-1024) by sectioning off an end of the tube and tapping
the open end into a bed of the sample. The loaded capillary was
mounted in a holder that was secured onto the x-y stage. A
diffractogram was acquired under ambient conditions at 46 kV and 40
mA in transmission mode, while oscillating about the omega-axis
from 0-5 degrees at 1 degree/s and spinning about the phi-axis at 2
degrees/s. The exposure time was 15 minutes unless otherwise
specified. The diffractogram obtained (Debye ring diffraction on
the image plate detector) was integrated over 2-theta from 2 to 60
degrees and chi (1 segment) from 0 to 360 degrees at a step size of
0.02 degrees using the cylint utility in the RINT Rapid Display
software (version 1.18, Rigaku/MSC). The dark counts value was set
to 8, normalization was set to average, and no omega, chi or phi
offsets were used for the integration. The integrated diffraction
patterns were analyzed using JADE XRD Pattern Processing software,
versions 5.0 and 6.0 (C)1995-2002, Materials Data, Inc.).
5.5.2. RESULTS
[0118] Using the DSC and TGA data obtained for Ritonavir Forms III,
IV, and V, and published data for Forms I and II, the different
thermal characteristics of each of the forms of Ritonavir were
determined. These characteristics are provided below in Table
1:
1 TABLE 1 TGA % weight loss Form m.p. (.degree. C.) (up to
130.degree. C.) Crystal Habit I 122 <0.3 lath II 125 <0.3
needles III 80 .+-. 2 30--60 needles IV 99 .+-. 2 4--9 needles V
116 .+-. 2 <0.3 lath
[0119] The data for Forms I and II were obtained from Chemburkar.
The difference in the thermal properties of the various forms of
Ritonavir is apparent from the conversion of Ritonavir(III) to
Ritonavir(IV), which is shown by DSC in FIG. 17.
[0120] Raman spectra of each of the five forms of Ritonavir are
shown in FIGS. 1, 3, 7, 11, and 15. Peaks distinctive of each form
using a dispersive Near-IR laser-based Raman spectrometer are
listed below in Table 2:
2 TABLE 4 Form Unique Raman Peaks (cm.sup.-1) I 428.1, 821.3,
928.1, 966.3, 982.7, 1033.2, 1452.5, 1444.2, 1461.9, 1647.9 II
417.4, 443.4, 579.9, 954.1, 1029.1, 1662.0 III 691.13, 1393.29 IV
1404.73 V 814.6, 963.7
[0121] The distinct nature of each of the forms of Ritonavir is
also evident from powder X-ray diffraction data. Graphical and
tabular X-ray diffraction data for each of the three forms of the
compound are provided in FIGS. 8, 12, and 16. Several peaks that
are distinctive to each form are listed below in Table 3:
3 TABLE 3 Form Unique X-ray Diffraction Peaks (degrees 2-Theta) III
3.1, 6.8, 7.7, 8.3, 9.2, 10.5, 12.1, 13.1 IV 3.1, 6.1, 9.2, 12.1,
13.8 V 3.4, 6.4, 9.9, 12.7, 13.6, 15.3, 15.8, 17.5
[0122] The difference between the forms is even more apparent from
FIG. 18, which provides a comparison of diffractograms obtained for
each of the forms of Ritonavir. These data show that Ritonavir(III)
and Ritonavir(IV) exhibit highly similar XRD patterns, which is
consistent with a conserved structure that is solvated in one form
(Ritonavir(III)) and partially (or essentially fully) desolvated in
another form (Ritonavir(IV)).
5.5. EXAMPLE 5
[0123] Conversion of Form V to Form I
[0124] Ritonavir(V) can transform into other forms of Ritonavir
under certain conditions. For example, if Ritonavir(V) is prepared
as above in Example 3, it was found to form a mixture of Forms V
and I when left in the crystallization mixture for a prolonged
period of time (hours to days). In a particular instance,
Ritonavir(V) that was left in the crystallization mixture for
approximately 16 hours at the nucleation temperature of 5.degree.
C. formed Ritonavir(I) as evidenced by X-ray diffraction (FIG. 19)
and DSC (FIG. 20).
[0125] While the invention has been described with respect to the
particular embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made without
departing from the spirit and scope of the invention as recited by
the appended claims.
* * * * *